CA1098447A - 2-.gamma.-(PIPERIDINO)-PROPYL-1,2-BENZISOTHIAZOL-3-ONE - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The compound 2-[8-(1-piperidinyl)propyl]-1,2-benzoisothiazol-3-one is disclosed which has exceptionally high activity in inhibitive platelet aggretion. Methods of preparation of the compound are also disclosed.

Description

1¢~'a84~7 This invention relates to antithrombotic compound in particular to a benzisothiazolone which has particularly h`igh acti~ity.
Arterial thrombosis develops intially from the aggregation of blood platelets within the artery. This aggregate may eventually lead to the formation of fibrin and the formation of a consolidated occlusive thrombus. The most widely used therapy for thrombosis is the use of anti-coagulant agents, which influence blood clotting~ However, although effective in venous thrombosis, where the thrombus is formed mainly of fibrin, anti-coagulant therapy has no effect on platelet aggregation and has therefore lim~ted effectivenesfi in arterial thrombosis. It is now accepted that anti-coagulant drugs have little to offer in the treatment of arterial thrombosis.
With the increasing recognition of the primary role of platelets in thrombosis, attention had turned to drugs which are capable of inhibiting the aggregation of platelets.
U.S. Patent Specification 3,227,715 discloses a class of benzi-sothiazolones of the formula (I`):- 0 Rl ~ - ~ - W (I) Wherein A represents a lower alkylene of 2 to 4 carbon atoms, Rl and R2 t are hydrogen or halogen, R3 and R4 represent hydrogen, lowex alkyl, cyclo- t ; 20 alkyl, hydroxyalkyl of 2 to 4 carbon atoms or alkoxyalkyl of 2 to 4 carbon atoms, and R3 and R4 together with the nitrogen atom on which they are sub- 5 stituted stand for an unsubstituted or lower alkyl substituted heterocyclic ring having from 5 to 6 atoms in the ring; as being useful for the therapy , 10~84~7 of inflammatory processes~
U.S. Patent 3,227,715 does not suggest any anti-thrombotic actiyity for any of the compounds described therein~ :
Our U.S. Patent 4,113,728 discloses a related class of benziso-thiazolones as being effective in inhibiting platelet aggregation.
We have now found that a benzisothiazolone compound which falls within the generic disclosure of U.S. Patent 3,227,715 but is not specifically described therein or in U~S. Patent 4,113,728, has exceptionally high activity in inhibiting platelet aggregation which is not predictable from the prior art, The present invention therefore provides the compound 2~~
piperidinyl)propyl]-1,2-benzisothiazol-3-one of formula (II, or a pharmaceut-ically accepta~le acid addition salt thereof: .

~ W - (C32)3 - ~ (Il) Suitable acid addition salts include inorganic salts such as ; sulphates, nitrate, phosphate, and borate, hydrohalides. e,g, hydrochloride, hydrobromide, and hydroiodide, and organic acid addition salts such as acetate, oxalate, tartrate, maleate~ citrate, succinate, benzoate, ascorbate, methanesulphonate, and p-toluenesulphonate~
; Preferr~d salts are the hydrochloride and hydrob~omide.
The compound of this invention may be prepared by reacting a compound of formula (III): ~ ~ CO.W

wherein W and Z are the same or d~fferent and each is a halogen atom;
' wi.th a compound of formula (IVl:

~. . .. : .
` , :'- .,~ :
,~ ~
.

' ~ ";' :

10"84~7 N~2 ' ~C~2) 3 - N3 (IY) Preferably W is chlorine and Z is chlorine or bromine. Suitable solvents for the reaction include carbon tetrachloride or other halogenated hydrocarbon solvents.
A second method for the preparation of the compound of formula (IIl comprises reaction of a compound of formula (V) or a salt thereof:

~, ~ NH ~V) with a compound of formula (VIl:

Q (- 2 3 ~ (VI) whe~ein Q ~ a readily displaceable group~ Suitably, Q is a halogen atom.
Preferably the compound (VIl is used as its alkali metal salt, for example the sodium salt.
In this reaction a solYent such as dimethyl formamide or dimethyl-sulphoxide may be used, preferably at elevated temperatures. In general the corresponding 3-ether is also formed and the desired product may be separated by crystallisation, distillation and chromatographic techniques.
Compound of formula (IIl may also be prepared by treating a compound of formula (VIIl:

(VII) NH.(CH213 - 2 : ~; :: ' 10~8~7 with either a base or with chlorine or bromine.
Suitable bases include 10% sodium hydroxide or other aqueous alkali and the reaction may be carried out at room temperature or elevated temperatures. If chlorine is employed in this reaction it may be bubbled into a solution of compound (VII~ in an inert solvent such as carbon tetra-chloride.
The compound of formula (II) may also be prepared by treating a compound of formula (VIII~: I
2Ra ~ S-NH-~CH2)3- N ~ (VIII) wherein C02R ~s a carboxylic ester group; with a base. t Suitably the group R is an alkyl or aryl group. Suitable bases for the react~on inc~ude alkali metal alkoxides, alkali metal hydroxides and tetramethyL~mmon~um hydroxide in lower alcohols.
The invention also provides a pharmaceutical composition which comprises a compound of formula ~II as defi`ned above together with at least one pharmaceutically acceptable carrier~
As~ ~5 common pract~ce, such composition will usually be accompanied by or associated with written or printed directions for use in the medical treatment concerned, in this case as an agent for the inhibition of platelet aggregation or thxombus formation~
The composition may be formulated for administration by any route, although an oral administration is preferred. The compositions may be in the form of tablets, capsules, powders, granulest lozenges, or liquid prepar-ations, such as oral or ster~le parenteral solutions or suspensions. I
Tablets and capsules for oral administration may be in unit dose _ 5 _ ~ t .`: ` : ' ~' ,. ~ ' ;, 10"8~7 presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinyl-pyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol, or silica; disintegrants, for example potato starch; or accepta'ole wetting agents such as sodium lauryl sulphate.
The tablets may be coated according to methods well known in normal pharmaceut-ical practice. Oral liquid preparations may be in the form of, for example, a~ueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl .. ..
cellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for~example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils~, for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol;
preservatiYeS~ for example methyl or propyl p-hydroxybenzoate sorbic acid, and if desired conYentional flavouring or colouring agents. The compound may also if desired be incorporated in a foodstuff, for example in the form of a biscuit, For parenteral administration~ fluid unit dosage forms are prepared util~zi`ng the compound and a sterile vehi~Le~, water being preferred. The compound, depending on the vehicle and concentration used, can be either sus-pended or dissolved in the vehicle, In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitaole vial or ampoule and sealing~ ~dvantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the ~98447 vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum~ The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection is supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and steriliza-tion cannot be accomplished by filtration. The compound can be sterili~ed by exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99% by weight, preferably from la-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 1 - 500 mg., of the active ingredient.
~ he dosage employed for adult treatment will of course depend on the dose-response characteris~ics of the particular active ingredient, and also on the blood volume and condition of the patient, but will normally be in the range 0~01 to 30 mg/kg~day depending on the route and frequency of admin~stration~ The preferred dose ~s 10 to 500 mg., orally 1 to 3 times a day for an adult human~
The compositions~of the invention are useful for administration to humans and animals to prevent clot formation for example after surgery to prevent postoperative thrombosis~ in geriatric patients to prevent transient cerebral ischemic attacks; and long-term prophylaxis following myocardial infarcts and strokes~
The compounds of formula (II1 may also have applications in the StQrage of wholé blood in blood banks, and whole blood to be used in heart-. . . I
lung machines~, or to be circulated through organs, e.g. heart and kidney, `
. .

. ~ :

~Q~8447 which have been removed from a cadaver and prior to transplant.
The following example illustrates the invention.

xample COCI O ~ Cl_ ~ ~ C

2 ( 2)3 3 ~ I

~ N (CH2)3 N~

Dry chlorine was passed into a suspension of 2,2'-dithiodibenzoyl 6 chloride (2.41g, 7.03 m. mole) in dry CC14 (50ml) until solution was complete.
Excess of chlorine was removed by passing nitrogen through the reaction mix-ture, the solution was filtered, and the filtrate was added dropwise with stirring to a solution of N-(3-aminopropyl)piperidine (6.0g, 42.25 m. mole) in dry CC14 (100 ml) at room temperature.
The reaction mixture was transferred to a separating funnel with - dichloromethane and the suspension was washed with 10% aqueous sodium hydrox-ide solution, water and brine. The organic layer was dried (anhydrous MgSO4¦~ evaporated, and the residue was chromatographed on silica gel (150 g) using dichloromethane-methanol ~90:101 as eluant.
A solution of the product in diisopropyl ether was treated with animal charcoal, filtered, evapQrated and the residue (c~1.3gl was re- }
crystalli`sed from diisopropyl ether giYing 2 ~-(piperidinol propyl-1,2-benz-i`'.`.. I

, '': "' - : , ~, ,. :

lQ"8447 ``

isothiazol-3-one as colourless needles~ 720mg, (18.5~, m~p 71,5 - 73 , Biological Data . _ _ Thecompoundsof the Example was tested for their ability to inhibit platelet aggregation in the guinea pig ex vivo by the method given below, and was compared with two closely related compounds disclosed in U.S. Patent

3,337,715, and also with two compounds disclosed in U.S. Patent 4,113,728, as well as with three known anti~aggregant compounds.
Method ._ ~
Ten male guinea pigs weighing 250-300g were orally dosed 1% methyl cellulose (5ml/kg~ in which the compound under test was suspended. Ten control animals were given methyl cellulose alone~ Two hours later, each animal was killed and 4~5ml blood dxawn from the ~nferior vena cava into 0~5ml trisodium .... - , citrate dihydrate. Platelet-rich-plasma (P~RP] was prepared from each blood sample by centrifugation at 450g for 5 min~ The platelet concentration in Y
each sample of PRP was adjusted with autologous platelet-poor plasma to give a count of 500,000 platelets~J~l PRP Aggregation was measured turbidometrically .. .... , O
(G.~R. Born, 1962 Nature, 194, 927-9291 at 37 using a Bryston aggregometer coupled to a pen recorder. The concentration of collagen producing approxi-mately 50% ma~imal aggregation and the concentration of ADP producing first-phase aggregation were compared in PRP samples from control and drug treated Y
animals. Results are s D arised in Table 1 together with some known anti-aggregant compounds for comparison.
In Table 1 the dose ratiorirepresents the ratio of the concen-tration of aggregating agent to cause aggregation in PRP from drug-treated animals to the concentration of aggregating agent to cause aggregation in PRP
from control animals~
Table 1 gives the results of the compound of this invention _ g _ ' ' . ,' . ,': : ' ~

, ~0'48447 (compound A), two compounds disclosed in U.S. Patent 4,113,728 (compounds B and C), two compounds disclosed in U.S. Patent 3,227,715 (compounds D and E) and three known anti-aggregant agents (compounds F,G,H).

Table 1 Compound Tested Oral Dose .Dose Ratio _ __ __ _ _ mmol/kg Collayen ADP

A. 2-~ -(l-piperidinyl) propyl~ -1,2-benzisothiazol-3-one 0.15727* 7 27*

B. 2-~ -(3-azabicyclo~3.2.2~-non-3-yl)ethyl~-1,2-benzisothiazol-3-one 0.15 1.7` 1.1 C. 5,6-dimethoxy-2-~-(2'-pyridyl)etny~ -1,2-benzisothiazol-3-one 0,15 1.5 1.1 D~ 2~L~(l-piperidyll-ethyl~
1,2-~enzisothiazol-3-one 0.15 ~18.2* 8.3*

E. 2-c~-(l-pyrrolidinyl)-ethyl]-1,2-benzlsothiazol-3-one 0.15 13.9* 1.9 F Sulfinpyrazone 0.3 2.1* 1.2 G. Aspirin 0.15 2.2* 1.3 20 H. 4-(4-morphol~ny~
2-(1-p~perzinyl~
thieno C3,2-d~,pyrimidine 0.15 3.0* 1.3 dihydrochloride It can be seen from Table I that compound A i5 many times more active than any other compound in Table 1 as an inhibitor of platelet aggregatlo~.

~-~-i - 1 0 .

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition having antithrombotic activity whlch comprises an antithrombotically-effective amount of the compound 2[y-(1-piperidinyl)propyl]-1,2-benzisothiazol-3-one or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutica:
ly acceptable carrier.

2. The composition of claim 1 in orally administrable form.

3. The composition of claim 1 or 2, wherein the compound or salt is present in an amount of from 1-500 mg as a unit dosage form.

4. The composition of claim 1, wherein the compound or salt is present in an amount of 0.1% to 99% by weight.

5. The composition of claim 4, wherein the compound or salt is present in an amount of from 10-60% by weight.